RESUMEN
The role of host genetic factors in the pathogenesis and outcome of hepatitis B virus (HBV) infection is not well known. We assessed the association of HLA and TNF (rs361525, rs1800629, rs1799724, rs1800630 and rs1799964) polymorphisms with HBV outcome in the South Indian population. Association of HLA polymorphism was analyzed in 90 individuals from each group, that is, spontaneous recovery (SR) and chronic-HBV (C-HBV) infection. The role of TNF polymorphisms was evaluated in 150 subjects with SR and 137 patients with C-HBV infection. After adjusting for age and sex, HLA-DRB1*07:01 was strongly associated with chronicity (corrected P-value (pc) <0.005, odds ratio (OR) 3.76, 95% confidence interval (CI) 1.84-7.68). The rs1800630 genotype was associated with HBV outcome in codominant (pc<0.01, OR=1.99, 95% CI 1.30-3.05) and dominant (pc<0.01, OR=2.28, 95% CI 1.35-3.84) analyzing models after adjusting for age and sex. Similarly, the rs1799964 genotype was associated with HBV outcome in codominant (pc=0.01, OR=1.57, 95% CI 1.09-2.27) and dominant (pc<0.01, OR=2.21, 95% CI 1.27-3.83) analyzing models. Haplotype analysis (rs1799964/rs1800630/rs1799724/rs1800629/rs361525) revealed that the CACGG haplotype was strongly associated with C-HBV infection (P=0.0004). Our study suggests that inheritance of HLA and TNF polymorphisms might explain the outcome of HBV infection in the South Indian population.
Asunto(s)
Antígenos HLA/genética , Hepatitis B/genética , Polimorfismo de Nucleótido Simple , Factor de Necrosis Tumoral alfa/genética , Adulto , Alelos , Pueblo Asiatico/genética , Femenino , Frecuencia de los Genes , Genotipo , Cadenas HLA-DRB1/genética , Hepatitis B Crónica/genética , Humanos , India , Desequilibrio de Ligamiento , Masculino , Persona de Mediana Edad , Evaluación de Resultado en la Atención de Salud , Pronóstico , Adulto JovenRESUMEN
HYPOTHESIS: Assessment of the prevalence and type distribution of human papillomavirus (HPV) in squamous cell carcinomas (SCC) of the cervix across India was undertaken to estimate the impact of available prophylactic HPV-L1 vaccines in the country and to find out additional types that might be needed to be incorporated in second-generation vaccines. METHODS: High-risk (HR) HPVs were genotyped from 667 histopathologically confirmed cases of SCC from 6 different centers representing 4 regions across India: Advanced Centre for Treatment, Research and Education in Cancer, Mumbai; All India Institute of Medical Sciences, New Delhi; Cancer Foundation of India, Kolkata; Christian Medical College, Vellore; Kidwai Memorial Institute of Oncology, Bangalore; and Regional Cancer Center, Thiruvananthapuram. Human papillomaviruses in tumor biopsies were analyzed by Xcytonscreen HPV based on PGMY09/11 multiplex polymerase chain reaction and reverse dot blot assay. RESULTS: Overall viral prevalence across India was not different; 92.1% of 667 cases harbored HPV; 8% were negative. Infection with single HR type was seen in 86.8%: predominant types being HPV-16 followed by HPV-18, -45, -73, -31, -56, -52, -58, -59, -33, -68, -51, -35, -26, and -39. Human papillomavirus types 16/18-positive fraction formed 79.6%; other types comprised 12.4%. CONCLUSIONS: Prophylactic HPV-16/18-L1 vaccines would provide greater than 75% protection against SCC in India. Ranking and frequencies of non-16/18 types were different from earlier reports. Hence, considering the possibility of promotion of persistence of nonvaccine types in the vaccinees due to original antigenic sin and the lack of organized screening programs in India, a broad-based vaccine approach would be appropriate.
Asunto(s)
Carcinoma de Células Escamosas/epidemiología , Carcinoma de Células Escamosas/virología , Infecciones por Papillomavirus/epidemiología , Neoplasias del Cuello Uterino/epidemiología , Neoplasias del Cuello Uterino/virología , Adulto , Distribución por Edad , Anciano , Anciano de 80 o más Años , Biopsia con Aguja , Carcinoma de Células Escamosas/patología , Estudios de Cohortes , ADN Viral/análisis , Femenino , Papillomavirus Humano 16/genética , Papillomavirus Humano 16/aislamiento & purificación , Papillomavirus Humano 18/genética , Papillomavirus Humano 18/aislamiento & purificación , Humanos , Inmunohistoquímica , India/epidemiología , Persona de Mediana Edad , Papillomaviridae/genética , Papillomaviridae/aislamiento & purificación , Infecciones por Papillomavirus/patología , Infecciones por Papillomavirus/prevención & control , Vacunas contra Papillomavirus/administración & dosificación , Reacción en Cadena de la Polimerasa , Lesiones Precancerosas/epidemiología , Lesiones Precancerosas/patología , Prevalencia , Medición de Riesgo , Neoplasias del Cuello Uterino/patología , Frotis VaginalRESUMEN
Mannose binding lectin (MBL) is an important innate immune system pattern recognition molecule. The MBL gene polymorphisms are reported to play a crucial role in outcome of hepatitis B virus (HBV) infection. In this study, we ascertained the association of MBL genotypes with HBV outcome in a South Indian population. The MBL gene polymorphisms at codons 52, 54 and 57 of exon I, and promoter polymorphisms at -221 were typed by polymerase chain reaction-sequence specific primer in spontaneously recovered and in chronic HBV group. The allele frequency of codon 52 'C' was significantly higher in chronic HBV group than in the recovered group (98.5% vs. 93.6%; P = 0.003) and codon 52 'T' was significantly higher in recovered group than in the chronic group (6.4% vs. 1.5%; P = 0.003). In multivariate analysis, after adjusting for age, sex and state of origin, codon 52 'CC' and 'CT' genotypes were significantly associated with chronicity and recovery respectively [odds ratio (OR), 0.25; 95% confidence interval (CI), 0.08-0.80, P = 0.02] in co-dominant analyzing models. This was re-affirmed in analysis performed exclusively on Tamil Nadu subjects (OR, 0.23; 95% CI, 0.06-0.93, P = 0.039). The frequency of low/none haplotype (XY/O) was significantly higher in recovered group than in chronic group (15.6% vs 7.5%) and associated with spontaneous recovery (OR, 2.28; 95% CI, 1.04-4.99, P = 0.035). Our results provide preliminary evidence that inheritance of codon 52 genotypes and XY/O haplotype associated with low MBL level substantially determine the outcome of HBV infection in a sympatrically isolated South Indian population.
Asunto(s)
Hepatitis B Crónica/genética , Hepatitis B/genética , Lectina de Unión a Manosa/genética , Polimorfismo de Nucleótido Simple/genética , Regiones Promotoras Genéticas/genética , Alelos , Femenino , Genotipo , Haplotipos , Hepatitis B/inmunología , Hepatitis B Crónica/inmunología , Humanos , India , Masculino , Análisis MultivarianteRESUMEN
Human papilloma virus is a causative factor in the etiology of cervical cancer with HPV16 being the most prevalent genotype associated with it. Intratype variations in oncogenic E6/E7 and capsid L1 proteins of HPV 16 besides being of phylogenetic importance, are associated with risk of viral persistence and progression. The objective of this multicentric study was to identify HPV-16 E6, E7 and L1 variants prevalent in India and their possible biological effects. Squamous cell cervical cancer biopsies were collected from 6 centres in India and examined for the presence of HPV 16. Variants of HPV-16 were characterized by full length sequence analysis of L1, E6 and E7 genes in 412 samples. Similar distribution of the variants was seen from the different centres/regions, with the European variant E350G being the most prevalent (58%), followed by American Asian variant (11.4%). Fifty six changes were seen in E6 region, 31 being nonsynonymous. The most frequent being L83V (72.3%), Q14H (13.1%) and H78Y (12.1%). Twenty-nine alterations were seen in E7 region, with 12 being nonsynonymous. The most frequent being F57V (9%). L1 region showed 204 changes, of which 67 were nonsynonymous. The most frequent being 448insS (100%), and 465delD (100%), H228D (94%), T292A (85%). The identified variants some new and some already reported can disrupt pentamer formation, transcriptional regulation of the virus, L1 protein interface interaction, B and T cell epitopes, p53 degradation, and thus their distribution is important for development of HPV diagnostics, vaccine, and for therapeutic purpose.
Asunto(s)
Proteínas de la Cápside/genética , Variación Genética , Papillomavirus Humano 16/genética , Proteínas Oncogénicas Virales/genética , Infecciones por Papillomavirus/genética , Proteínas Represoras/genética , Neoplasias del Cuello Uterino/genética , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/virología , Femenino , Papillomavirus Humano 16/clasificación , Humanos , India , Persona de Mediana Edad , Proteínas E7 de Papillomavirus , Infecciones por Papillomavirus/epidemiología , Infecciones por Papillomavirus/virología , Neoplasias del Cuello Uterino/virologíaRESUMEN
Cervical cancer is one of the most common cancers in women worldwide, particularly in developing countries. The viral origin of cervical cancer has been proven beyond any reasonable doubt. Persistent infection with certain subsets of human papillomaviruses is recognized as a necessary cause for the development of cervical cancer. Persistence of oncogenic HPVs, immunodeficiency, high HPV viral load and cofactors like smoking, multiple sex partners and poor nutrition predispose to cervical cancer. Prophylactic vaccines using HPV virus-like particles containing capsid protein L1 have shown protection against disease in animals and are currently undergoing clinical trials. Therapeutic vaccines using HPV E6 and E7 proteins are also being investigated for their ability to remove residual infection.